The broad, long-term objective of this proposal is to understand how cancer evades and disarms the mmune system at the molecular, cellular and organism level so this process can be interrupted for the successful prevention of primary or recurrent cancer. This P01 competitive renewal application primarily investigates the human innate immune system and Project 3, while integrated with the efforts of Projects 1, 2 and 4, is focused on natural killer (NK) cells. Work with cancer patients receiving T-cell depleted HLA haplo- identical inhibitory killer immunoglobulin like receptor (KIR)-mismatched allogeneic stem cell transplant provides direct evidence that NK cells have a graft versus leukemia effect that correlates with improved survival. Understanding the molecules that regulate NK cell development and function at the molecular, cellular and organism level will be critical to effectively manipulate the immune system for the prevention and treatment of cancer. Two of the many molecules that appear important in NK cell responsiveness to the development of cancer are transforming growth factor beta (TGF-(3) and inhibitory KIRs. Specifically, this proposal will: 1) Investigate the basic mechanisms by which TGF-p exerts its effects on NK cell development and NK cell function. For these studies we will use fresh secondary lymphoid tissue (i.e., tonsils and lymph nodes) where human NK cells develop, along with fresh human blood as a source of primary mature NK cells. 2) Perform two clinical trials in which patients with melanoma, renal carcinoma and pancreatic cancer will receive a "first-in-man" therapy of neutralizing antibody against TGF-p. 3) Perform a third clinical trial in which patients with multiple myeloma will receive an antibody that has broad recognition of inhibitory KIR. In each of these three trials, we will use patients with existing cancer who have failed conventional therapy, and thus we will have the opportunity, with our P01 colleagues, to assess human NK cell development and function in vivo before, during and after these novel and potentially immune modulating therapies are delivered. Collectively, this work will synergize with Cores A, B, and C and with Projects 1, 2, and 4 of this P01 competitive renewal application to better understand human innate immune development and function as it occurs normally and in cancer patients. It will provide new insights as to how innate immune effector cells may be modulated in order to prevent cancer or its recurrence.